Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation

Abstract

Keratins are obligate heterodimer proteins that form the intermediate filament cytoskeleton of all epithelial cells. Keratins are tissue and differentiation specific and are expressed in pairs of types I and II proteins. The spectrum of inherited human keratin diseases has steadily increased since the causative role of mutations in the basal keratinocyte keratins 5 and 14 in epidermolysis bullosa simplex (EBS) was first reported in 1991. At the time of writing, mutations in 15 epithelial keratins and two trichocyte keratins have been associated with human diseases which include EBS, bullous congenital ichthyosiform erythroderma, epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, diffuse and focal non-epidermolytic palmoplantar keratoderma, pachyonychia congenita and monilethrix. Mutations in extracutaneous keratins have been reported in oral white sponge naevus and Meesmann's corneal dystrophy. New subtleties of phenotype-genotype correlation are emerging within the keratin diseases with widely varying clinical presentations attributable to similar mutations within the same keratin. Mutations in keratin-associated proteins have recently been reported for the first time. This article reviews clinical, ultrastructural and molecular aspects of all the keratin diseases described to date and delineates potential future areas of research in this field.

Defining the Properties of the Nonhelical Tail Domain in Type II Keratin 5: Insight from a Bullous Disease-causing Mutation

“…Characterization of the properties of some of these mutant proteins has helped further our understanding of IF assembly, regulation, and function. Generally, severity of the clinical presentation correlates with the impact exerted by the mutation on the assembly and structure of keratin IFs in vitro and in vivo (Letai et al, 1993;Irvine and McLean, 1999;Porter and Lane, 2003;Omary et al, 2004). In recent years, the genetic basis of rarer forms of EBS was found to involve a distinct group of target genes, including plectin, integrin ␤4, and BP180 (Chavanas et al, 1996;Pulkkinen et al, 1996;Smith et al, 1996;Huber et al, 2002;Jonkman et al, 2002;Fontao et al, 2004), or a different type of mutation in the K5 gene.…”

“…Characterization of the properties of some of these mutant proteins has helped further our understanding of IF assembly, regulation, and function. Generally, severity of the clinical presentation correlates with the impact exerted by the mutation on the assembly and structure of keratin IFs in vitro and in vivo (Letai et al, 1993;Irvine and McLean, 1999;Porter and Lane, 2003;Omary et al, 2004).…”

Keratin mutation primes mouse liver to oxidative injury†

“…Keratin mutations cause a variety of skin (K1/K5/K10/K14), oral/esophageal (K4/ K13), and ocular (K3/K12) diseases and are associated with cryptogenic and noncryptogenic forms of end-stage liver disease (K8/K18). [4][5][6] Involvement of keratin mutations with human disease, as a cause or predisposition, was initially suggested by the results of animal studies in which mutant keratins expressed in transgenic mice resulted in phenotypes that mirrored several human diseases. 3,7,8 For example, transgenic mice that overexpressed a K14 deletion mutant developed a blistering skin disease 9 that led to identifying mutations in K14 or its partner K5 as the cause of epidermolysis bullosa simplex.…”

Genética Molecular das Epidermólises Bolhosas

“…5 Existe uma forma intermediária com bolhas disseminadas, mas com quadro menos intenso do que o da EBS-DM, denominado EBS -Koebner (EBS-K), que certos autores consideram variante leve da EBS-DM. 7 A camada basal diferencia-se de outros epitélios e dos segmentos suprabasais da epiderme pela expressão das citoqueratinas 5 e 14.…”